Cushing syndrome, a fatal disease, is suspected in many thousands of patients each year, but confirmed in only a fraction of these. This project seeks to accurately identify which patients have Cushing syndrome, to define the etiology of their disease and to treat it optimally. There is no test that reliably separates individuals with pseudo-Cushing states, who have mild hypercortisolism and minimal physical features of Cushing syndrome, from those with mild or intermittent Cushing syndrome, who may present in an identical fashion. We have exploited the differences in pathophysiology of the pseudo-Cushing and Cushing syndrome states to develop new tests for this distinction. The hypercortisolism of patients with pseudo-Cushing syndrome reflects hypersecretion of CRH, suggesting that inhibition of the CRH neuron by dexamethasone, a potent glucocorticoid, would blunt the ACTH and cortisol responses to exogenous CRH. We have shown previously that patients with pseudo-Cushing syndrome have serum cortisol less than 1.4 ug/dL at 15 minutes after CRH, a criterion with 100 % specificity. We next explored whether these patients might be distinguished from patients with Cushing syndrome by inferior petrosal sinus sampling with CRH infusion, and demonstrated that this test does not discriminate well between the groups and should not be used for this purpose. Our second initiative, to improve the approach to the differential diagnosis of Cushing syndrome, focused on characterization of the oCRH stimulation test. This retrospective analysis of 112 patients with ACTH- dependent Cushing syndrome set criteria yielding 93% sensitivity and 100% specificity for the diagnosis of Cushing disease. Our third aim is to improve the therapy of these patients. Recent work evaluated the efficacy of early repeat transsphenoidal exploration in the setting of persistent hypercortisolism. 12 of 17 patients had remission of hypercortisolism after a second procedure, suggesting that this approach is an alternative to radiation therapy or adrenalectomy with the advantage of low morbidity and immediacy of cure. We also examined the natural history of 10 patients with ACTH-secreting islet cell tumors. Our retrospective experience indicates that patients presenting with this etiology of Cushing syndrome have malignant disease at the time of diagnosis. Thus, this subtype of ectopic ACTH secretion appears not to be occult, and should not be sought exhaustively in the patient with an unknown source of ACTH secretion.